Intestinal L-cell mechanoreception regulates hepatic lipid metabolism through GLP-1

Glucagon-like peptide-1 (GLP-1), secreted by intestinal L cells, is essential for lowering postprandial glucose levels and regulating hepatic lipid metabolism.We investigate the effects of manipulating Piezo1 in L cells on hepatic lipid metabolism. We found that normal and high-fat diet-fed L cell-specific <i>Piezo1</i> knockout (<i>IntL-Piezo1^-/-</i>) mice exhibited reduced circulating GLP-1 levels, increased hepatic lipid accumulation, decreased β-catenin expression, and elevated lipogenesis-related genes and proteins, including SREBP1c, PPARγ, FASN, and ACC. Treatment with exendin-4 improved fatty liver in <i>IntL-Piezo1^-/-</i> mice by stimulating β-catenin and inhibiting de novo lipogenesis. Intestinal bead implantation stimulated GLP-1 release and inhibited lipid synthesis in livers of diet-induced obese mice but not in <i>IntL-Piezo1^-/-</i> mice. In primary hepatocytes derived from <i>IntL-Piezo1^-/-</i> mice, lipid accumulation and enhanced fatty acid synthesis were associated with reduced β-catenin expression and impaired nuclear translocation. Exendin-4 treatment alleviated lipid accumulation, which was blocked by the β-catenin inhibitor nitazoxanide. L-cell mechanoreception is vital for regulating hepatic lipid metabolism through GLP-1.